Foxp3+ regulatory T cells: Differentiation specification subphenotypes

Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.
Nature Immunology (Impact Factor: 24.97). 08/2009; 10(7):689-95. DOI: 10.1038/ni.1760
Source: PubMed

ABSTRACT Regulatory T cells (T(reg) cells) characterized by expression of the transcription factor Foxp3 play a key role in immune homeostasis. Rather than a monomorphic population strictly determined by Foxp3 as a 'master regulator', the emerging view is one of T(reg) cells as a population with many levels of complexity. Several regulatory factors partake in the control of their transcriptional 'signature', with Foxp3 being a key regulator but insufficient and unnecessary to specify all aspects of the lineage. Distinct subphenotypes of Foxp3+ T(reg) cells are found in different anatomical locations. Some subphenotypes specifically control different facets of effector T cell function and, perhaps surprisingly, share transcriptional control elements with the very cells they regulate. This review will focus on these novel aspects of T(reg) cell diversity.

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    • "FoxP3 + regulatory T (Treg) cells restrain the immune responses to self-antigens, pathogens, allergens, and commensal microorganisms (Feuerer et al., 2009; Josefowicz et al., 2012a). Treg cells are produced in the thymus (tTreg) but may also be generated in the periphery (pTreg) or in vitro (iTreg) by conversion of naive conventional T (Tconv) cells (Curotto de Lafaille and Lafaille , 2009; Yadav et al., 2013). "
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    ABSTRACT: Regulatory T (Treg) cells expressing the transcription factor forkhead box P3 (FoxP3) control immune responses and prevent autoimmunity. Treatment with glucocorticoids (GCs) has been shown to increase Treg cell frequency, but the mechanisms of their action on Treg cell induction are largely unknown. Here, we report that glucocorticoid-induced leucine zipper (GILZ), a protein induced by GCs, promotes Treg cell production. In mice, GILZ overexpression causes an increase in Treg cell number, whereas GILZ deficiency results in impaired generation of peripheral Treg cells (pTreg), associated with increased spontaneous and experimental intestinal inflammation. Mechanistically, we found that GILZ is required for GCs to cooperate with TGF-β in FoxP3 induction, while it enhances TGF-β signaling by binding to and promoting Smad2 phosphorylation and activation of FoxP3 expression. Thus, our results establish an essential GILZ-mediated link between the anti-inflammatory action of GCs and the regulation of TGF-β-dependent pTreg production.
    Cell Reports 04/2014; 7(2). DOI:10.1016/j.celrep.2014.03.004 · 7.21 Impact Factor
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    • "Cells which survive the selection are exported to the periphery as CD4 + helper or CD8 + cytotoxic single positive (SP) naïve cells where they are ready for antigenic challenge and differentiation into effector cells (Stritesky et al., 2012). Importantly, besides these two major cell subsets, regulatory T cells are also generated which play a crucial role in suppressing and controlling autoimmunity (Feuerer et al., 2009). The selection process is extremely important in generating a functional T cell repertoire and deficiencies in this process may lead to defective immune tolerance and autoimmunity (von Boehmer and Melchers, 2010). "
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    ABSTRACT: Systemic glucocorticoids (GCs) mainly originate from de novo synthesis in the adrenal cortex under the control of the hypothalamus-pituitary-adrenal (HPA)-axis. However, research during the last 1-2 decades has revealed that additional organs express the necessary enzymes and have the capacity for de novo synthesis of biologically active GCs. This includes the thymus, intestine, skin and the brain. Recent research has also revealed that locally synthesized GCs most likely act in a paracrine or autocrine manner and have significant physiological roles in local homeostasis, cell development and immune cell activation. In this review, we summarize the nature, regulation and known physiological roles of extra-adrenal GC synthesis. We specifically focus on the thymus in which GC production (by both developing thymocytes and stromal cells) has an important role in the maintenance of proper immunological function.
    Molecular and Cellular Endocrinology 05/2013; DOI:10.1016/j.mce.2013.05.007 · 4.24 Impact Factor
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    • "Under these conditions, anti-CD28 stimulation supported the production of endogenous IL-2. In contrast, other studies showed that costimulation through CD28 can inhibit aTreg differentiation, most likely via the PI3K– mTOR pathway (Feuerer et al., 2009; Merkenschlager and von Boehmer, 2010). Therefore, the use of anti-CD28 for aTreg generation introduces additional complexity that may be difficult to define. "
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    ABSTRACT: Type 1 diabetes (T1D) results from autoimmune destruction of insulin-producing β-cells in the pancreatic islets. There is an immediate need to restore both β-cell function and immune tolerance to control disease progression and ultimately cure T1D. Currently, there is no effective treatment strategy to restore glucose regulation in patients with T1D. FoxP3-expressing CD4(+) regulatory T cells (Tregs) are potential candidates to control autoimmunity because they play a central role in maintaining self-tolerance. However, deficiencies in either naturally occurring Tregs (nTregs) themselves and/or their ability to control pathogenic effector T cells have been associated with T1D. Here, we hypothesize that nTregs can be replaced by FoxP3(+) adaptive Tregs (aTregs), which are uniquely equipped to combat autoreactivity in T1D. Unlike nTregs, aTregs are stable and provide long-lived protection. In this review, we summarize the current understanding of aTregs and their potential for use as an immunological intervention to treat T1D.
    Journal of Molecular Cell Biology 11/2011; 4(1):38-47. DOI:10.1093/jmcb/mjr040 · 8.43 Impact Factor
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